Part II: Factors Driving Global Shortages of GLP-1RA Medications and access to Type 2 Diabetes Treatmen I Medicines for Africa I Utano Newsletter

Last week Utano Newsletter spotlighted that South Africa has been experiencing ongoing shortages of insulin pens since the beginning of 2024, that patients are being put back on human insulin a more complex medication and away fro GLP-1-RA in South Africa and how these shortages are affecting patients in Europe, the US and Australia. That in markets where GLP-1RA are not registered and where shortages of insulin are also occurring like Kenya, counterfeited versions of GLP-1RA for treatingg diabetes are approving and putting the safety of patients at great risk. In part II, we examine the factor that are driving these global shortages and what the future holds for type 2 diabetes patients and for patient access to these meolecules in general.

The drama and controversy surrounding high unmet medical needs for Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) – a class of medications developed to treat type 2 diabetes makes one wonder whether this is a unique moment in the annals of medical history. This class of molecules are effective at lowering glucose concentration in the blood compared to daily injection with insulin. They transformed injectable treatment for type 2 diabetes. Some of them can be used at a much lower frequency like once a week, and thus further simplifies treatment and elevating their appeal to patients. For people with diabetes, these molecules have a lower risk of causing hypoglycemia - a dangerous drop in blood sugar.

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But GLP-1RA are not used only to treat type 2 diabetes. They have another therapeutic use. Scientists discovered that when GLP-1RA are used at higher doses, they can also be associated with significant weight loss. They effectively promote weight loss in people with obesity. Consequently, pharma companies began marketing high dose GLP1-RA formulations for treating obesity under different brand names. For example, the once-a-week GLP1-RA semaglutide initially sold as 0.5 mg and 1 mg Ozempic for managing type 2 diabetes is now sold in 2.4mg dosages as Wegovy for managing obesity. GLP-1RA have become the miracle treatment for individuals suffering from recalcitrant obesity – the kind that is resistant to control with dietary and lifestyle modifications. GLP-1RA have enabled this particular group of patients achieve sustained weight loss.

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That GLP-1RA can cause significant weight loss has appended the availability of thia treatment for diabetes by creating competing use of this medication. So high has been the demand for Wegovy that manufacturing capacity has not managed to keep up. As a result, supplies have dwindled leaving physicians faced with obesity patients clamoring for the miracle treatment of which there just is not enough. To circumvent shortages, physicians and their patients turned towards medications specifically registered and recommended for diabetic patients under national treatment guidelines. Physicians have been prescribing the diabetic medication – Ozempic - off-label to initiate weight loss. In the context of already ongoing shortages of GLP-1RA treatment for diabetes, the result has been that low dose formulations that treatment guidelines recommend specifically to treat diabetic patients have become the medication of choice for those seeking to lose weight.

Whilst obesity is a health problem that can cause serious health complications, according to the European Medicines Agency, there is evidence suggesting that not all patients receiving weight loss treatment are clinically obese. In individuals who are not clinically obese, it can be managed with life style and dietary changes something that cannot be easily done for insulin requiring type 2 diabetes. Regulators have expressed concerns that there are strong indications that people without type 2 diabetes and who are not clinically obese are being prescribed these medications as a quick fix to losing weight ?in situations where lifestyle or dietary changes would be recommended to improve weight loss. The impact of this has been to widen the gulf of unmet medical needs. It has added a burden on a supply environment that is already under tremendous pressure and struggling to cope with existing demand for type 2 diabetes treatment. This elevated demand for GLP-1RA to treat obesity has fueled widespread shortages in GLP-1RA and exacerbated insulin shortages. In some cases, diabetes can also be managed with adjustments to lifestyle. Whilst weight loss can also be an objective when treating type 2 diabetes patients, on its own, it may not be enough for some patients.

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The semaglutide domino effect

More broadly, global shortages of semaglutide have had a knock-on effect on the availability of alternative GLP-1RA such as dulaglutide (Trulicity) and liraglutide (Victoza). They too are now experiencing limited availability for the same reason. They are also being used to fill the gap in Ozempic availability, which is being used to fill the gap left by Wegovy shortages. Increased demand for another GLP-1RA – exenatide has also led to plans to discontinue its production exacerbating the supply gap. Introduction of new GLP-1/GIP agonist (Mounjaro) for treatment of type 2 diabetes in some markets like Australia have been delayed until adequate supply can be assured. This has also been as a result of its increased use as an alternative to Ozempic. It’s pending approval by the US FDA for obesity management will result in it being a competition for Wegovy and possibly improve treatment availability.

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Critical shortages for medicines essential for type 2 diabetes management like insulin and GLP-1RA highlight why it is necessary to expand manufacturing capacity. It is a big challenge that there are only three major suppliers of insulin - Novo Nordisk, Eli Lilly and Sanofi whom between them have 90% share of the global market for insulin. In order to solve shortages of diabetes treatment, major pharma companies would need to build more manufacturing facilities. Alternatively, they can license production of these products and contract manufacture so that a greater number of manufacturers are available to produce these medications and help to expand the supply base enough to achieve security of supply of a life-saving diabetes treatment. Disruption of production of life-saving diabetes medications like GLP-1RA and insulin have grave consequences for patients suffering from such a serious chronic condition like diabetes.

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Adding fuel to the fire with social media

Regulators have also highlighted other concerns about what is worsening widespread shortages. For instance, the European Medicines Agency has said that there are indications that pharma companies may be engaging in unapproved advertising practices. In many countries pharmaceutical advertising indirectly promoting medicine for treating diseases is prohibited. That it is happening has raised the need for EMA regulators to find a way to regulate advertising practices relating to these molecules. According to Emer Cooke, the CEO of the European Medicines Agency, regulators in Europe are currently trying to work out how to regulate unapproved marketing campaigns as well as the unsolicited promotion of GLP-1RA by social media influencers. Influencers have become a major driver of what regulators consider the cosmetic use of GLP-1RA for weight loss purposes by individuals who are not clinically obese. According to the EMA, such unregulated promotion can be dangerous because GLP-1RA are not harmless. EMA regulators are drawing attention to the fact that GLP-1RA have side effects that can be quite serious. For instance, Wegovy can cause side effects like thyroid tumors and cancer, inflammation of the pancreas, kidney failure, depression and suicide.

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The fact that people who are not in medical need are using up a medication for patients who need the treatment for a more serious illness has raised ethical questions about who is more deserving. On the one hand there are patients for which the medication is indicated who need it to survive. On the other hand, there are those who are using this medication to lose weight even though they may not have a medical condition that justifies use. Regulators are trying to work out how to ensure that patients for whom the medication is indicated are prioritizes. EMA regulators have indicated that they are trying to find a way to balance the demand for clinical diabetes treatment – an illness that require appropriate treatments lack of which can cause serious associated complications. Regulators in Europe and in Australia, have given clear guidelines that Ozempic should be reserved for type 2 diabetes patients. In some countries, treatment guidelines recommend that GLP-RA should be considered the preferred injectable therapy for type 2 diabetes in most cases. Some experts have suggested that similar policies will be needed in the South African context to address similar challenges. In the short term however, the problem remains that the guidelines will do little to improve the situation when patients cannot get the medication anyway.?

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There are many factors in play that could worsen availability even further. For instance, in some countries, insurance companies are not supporting the use of GLP-1RA medications for treating obesity. That limits access to those who can afford to pay out of pocket. If that changes, demand will likely grow. Then there is the possibility of expanding the target population. GLP-1RA products have not been tested for children and that currently excludes this group. However, in the US, the pediatric association has indicated that with such a serious childhood obesity epidemic, it is no longer justifiable not to prescribe GLP-1RA to children because the potential benefits are likely to outweigh the severe health complications of obesity. Expanding therapeutic applications of this class of molecules can be expected to increase demand. Emerging scientific evidence is that this class of medications is showing great promise at reducing heart attacks and strokes and perhaps even mental illnesses. Without significant scale up of manufacturing capacity, to meet the demands of an expanding patient population and therapeutic applications, all these factors will create a perfect storm that further limits treatment availability for diabetic patients.

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